The incidence of viral upper respiratory disease, the common cold, is immense. It has been estimated that nearly a billion cases annually appear in the United States alone. Rhinovirus, a member of the picornaviridae family, is the major cause of the common cold in humans. Since more than 110 strains of rhinovirus have been identified, the development of a comprehensive rhinovirus vaccine is not practical. Accordingly, chemotherapy appears to be a more desirable approach. Another member of the picornavirus family is the enterovirus, which includes approximately eighty human pathogens. Many of these enteroviruses cause cold-like symptoms; others can cause more serious diseases such as polio, conjunctivitis, aseptic meningitis and myocarditis.
Illness related to rhinovirus infection is evidenced by nasal discharge and obstruction. Furthermore, it has been implicated in otitis media, predisposes the development of bronchitis, exacerbates sinusitis, and has been implicated in the precipitation of asthmatic disease. Although it is considered by many to be a mere nuisance, its frequent occurrence in otherwise healthy individuals and the resulting economic importance has made rhinovirus infection the subject of extensive investigation.
The ability of chemical compounds to suppress the growth of viruses in vitro may be readily demonstrated using a virus plaque suppression test or a cytopathic effect test (CPE). Cf Siminoff, Applied Microbiology, 9(1), 66 (1961). Although a number of chemical compounds that inhibit picornaviruses have been identified, many are unacceptable due to 1) limited spectrum of activity, 2) undesirable side effects or 3) inability to prevent infection or illness in animals or humans. See Textbook of Human Virology, edited by Robert B. Belshe, chapter 16, "Rhinoviruses," Roland A. Levandowski, 391-405 (1985). Thus, despite the recognized therapeutic potential associated with a rhinovirus inhibitor and the research efforts expended thus far, a viable therapeutic agent has not yet emerged. For example, antiviral benzimidazole compounds have been disclosed in U.S. Pat. Nos. 4,008,243, 4,018,790, 4,118,573, 4,118,742 and 4,174,454.
Accordingly, the present invention provides novel pyridoimidazole compounds which inhibit the growth of picornaviruses, such as rhinoviruses (bovine and human) and the like, enteroviruses such as polioviruses and the like, coxsackieviruses of the A and B groups, or echo virus, cardioviruses such as encephalomyocarditis virus (EMC) and the like, apthoviruses such as foot and mouth disease virus and the like, and Hepatitis viruses such as Hepatitis C virus and the like.